Sandbox: TMNG

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Ahmed Younes M.B.B.CH [2]

Pathophysiology

• Toxic Multinodular Goiter (TMNG) is the result of hyperfunctioning thyroid follicles that are producing excess of thyroid hormones.
• TMNG develops on top of hypertrophied thyroid from prolonged (due to iodine deficiency or any cause of primary hypothyroidism). Low T3 and T4 levels cause prolonged TSH stimulation which causes hypertrophy of the thyroid gland and the development of focal or diffuse hyperplasia.
• Some of the nodules might develop hyperplasia and autonomous activity while others might degenerate, bleed and calcify.
• After the gland has undergone global activation and hyperplasia. Thyrotoxicity develops due to focal epithelial cell proliferation and thyroxine secretion.
• Hyperplastic gland is more likely to develop toxic goiter due to the following factors:

• With high proliferation rate in the hyperplastic gland, there might be transcription errors that go unchecked. This gives rise to a variety of mutations including mutations leading to activation of cAMP such as TSH-R and Gsα mutations.
• The process of synthesis of thyroxines involves the production of H2O2 and other free radicals, increasing the chance of developing mutations.
• A thyroid gland under the stress of over proliferation (in response to a state of hypothyroidism and excessive TSH stimulation) has increased growth factor expression. After resolution of the stimulus, the proliferating follicles continue to produce thyroxines even after the TSH stimulus ceases. Moreover, cells having the mutations will continue to produce cells having the same mutations.

Historical perspective

• Goiter was first seen in the inhabitants of Alps. They documented that consuming sea weeds caused improvement of the condition (which is supports the theory that the goiter was due Iodine deficiency).
• Goiter was described in Ancient Greece also and was called “Broncholcele”. This was 200 years before the discovery of thyroid gland.
• In 1850, Consuming Iodine as a preventive measure from goiter was suggested and this was the basis of providing Iodine in the meals provided to the students.
• In 1884, thyroidectomies were tried successfully for treatment of goiter.
• In a 2000 thyroidectomies performed by Kocher in the 19th century, the mortality rate was reported as 5%.

Classification

• A "diffuse goitre" is a goitre that has spread through all of the thyroid. It can be

• Simple goitre"
• multinodular goitre").

• "Toxic goitre" refers to goitre with hyperthyroidism. These most commonly due to Graves disease, but can be caused by inflammation or a multinodular goitre.
• "Nontoxic goitre" (associated with normal or low thyroid levels) refers to all other types (such as that caused by lithium or certain other autoimmune diseases).

Causes

• Hashimoto's thyroiditis
• Graves-Basedow disease
• Inborn errors of thyroid hormone synthesis, causing congenital hypothyroidism
• Thyroiditis (acute, chronic)
• Side-effects of pharmacological therapy
• Thyroid cancer

Differentiating toxic nodular goiter from other diseases

Toxic multinodular goiter must be differentiated from other diseases that cause hyperthyroidism and neck mass such as Graves' disease and thyroiditis

Cause of thyrotoxicosis	TSH receptor Antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	↓	-
Amiodarone induced thyroiditis-Type 1	-	Diffuse or nodular goiter	↓/Normal/↑	↓ but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	-	Normal	Absent	↓/absent	High urinary iodine
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/↑	↑	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/↑	↑	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	↓	↓ serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	↓	Abdominal RAIU